Breastfeeding and risk of childhood brain tumors: a report from the Childhood Cancer and Leukemia International Consortium.

PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies. RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses. CONCLUSION: Our data suggest that breastfeeding does not protect against CBT.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Allergies, genetic polymorphisms of Th2 interleukins, and childhood acute lymphoblastic leukemia: The ESTELLE study.

CONTEXT: A negative association between a history of allergy and childhood acute lymphoblastic leukemia (ALL) has been reported in previous studies, but remains debated. This work aimed to investigate this association accounting for genetic polymorphisms of the Th2 pathway cytokines (IL4, IL10, IL13, and IL4R). METHODS: Analyses were based on the French case-control study ESTELLE (2010-2011). The complete sample included 629 ALL cases and 1421 population-based controls frequency-matched on age and gender. The child's medical history was collected through standardized maternal interview. Biological samples were collected, and genotyping data were available for 411 cases and 704 controls of European origin. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. RESULTS: In the complete sample, a significant inverse association was observed between ALL and reported history of allergic rhinitis or sinusitis (OR = 0.65 [0.42-0.98]; P = 0.04), but there was no obvious association with allergies overall. There was an interaction between genetic polymorphisms in IL4 and IL4R (Pinteraction = 0.003), as well as a gene-environment interaction between IL4R-rs1801275 and a reported history of asthma (IOR = 0.23; Pint  = 0.008) and eczema (IOR = 0.47; Pint  = 0.06). We observed no interaction with the candidate polymorphisms in IL4 and IL13. CONCLUSION: These results suggest that the association between allergic symptoms and childhood ALL could be modified by IL4R-rs1801275, and that this variant could also interact with a functional variant in IL4 gene. Although they warrant confirmation, these results could help understand the pathological mechanisms under the reported inverse association between allergy and childhood ALL.

Investigating the inequalities in route to diagnosis amongst patients with diffuse large B-cell or follicular lymphoma in England.

INTRODUCTION: Diagnostic delay is associated with lower chances of cancer survival. Underlying comorbidities are known to affect the timely diagnosis of cancer. Diffuse large B-cell (DLBCL) and follicular lymphomas (FL) are primarily diagnosed amongst older patients, who are more likely to have comorbidities. Characteristics of clinical commissioning groups (CCG) are also known to impact diagnostic delay. We assess the association between comorbidities and diagnostic delay amongst patients with DLBCL or FL in England during 2005-2013. METHODS: Multivariable generalised linear mixed-effect models were used to assess the main association. Empirical Bayes estimates of the random effects were used to explore between-cluster variation. The latent normal joint modelling multiple imputation approach was used to account for partially observed variables. RESULTS: We included 30,078 and 15,551 patients diagnosed with DLBCL or FL, respectively. Amongst patients from the same CCG, having multimorbidity was strongly associated with the emergency route to diagnosis (DLBCL: odds ratio 1.56, CI 1.40-1.73; FL: odds ratio 1.80, CI 1.45-2.23). Amongst DLBCL patients, the diagnostic delay was possibly correlated with CCGs that had higher population densities. CONCLUSIONS: Underlying comorbidity is associated with diagnostic delay amongst patients with DLBCL or FL. Results suggest a possible correlation between CCGs with higher population densities and diagnostic delay of aggressive lymphomas.

Increased Risk of Parkinson's Disease in Women after Bilateral Oophorectomy.

BACKGROUND: Results regarding the association between hormonal exposure and risk of Parkinson's disease (PD) are heterogeneous. OBJECTIVES: To investigate the association of reproductive life characteristics with PD among postmenopausal women. METHODS: The PARTAGE case-control included 130 female cases and 255 age-matched female controls. Information on gynecological history was obtained from a standardized questionnaire and PD was validated by neurological examination. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. RESULTS: After adjustment for education level, smoking status, professional exposure to pesticides, and coffee and alcohol drinking, bilateral oophorectomy (OR = 3.55, 95%CI = 1.75-7.20), but neither menopause before age 50 years (OR = 1.24, 95%CI = 0.74-2.09) nor hormone therapy (HT; OR = 1.07, 95%CI = 0.62-1.86), was associated with PD. CONCLUSION: Our findings suggest that bilateral oophorectomy is associated with increased risk of PD. © 2021 International Parkinson and Movement Disorder Society.

Maternal Infection in Pregnancy and Childhood Leukemia: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the published evidence regarding the association between maternal infection during pregnancy and childhood leukemia. STUDY DESIGN: In this systematic review and meta-analysis (PROSPERO number, CRD42018087289), we searched PubMed and Embase to identify relevant studies. We included human studies that reported associations of at least one measure of maternal infection during pregnancy with acute lymphoblastic leukemia (ALL) or all childhood leukemias in the offspring. One reviewer extracted the data first using a standardized form, and the second reviewer independently checked the data for accuracy. Two reviewers used the Newcastle-Ottawa Scale to assess the quality of included studies. We conducted random effects meta-analyses to pool the ORs of specific type of infection on ALL and childhood leukemia. RESULTS: This review included 20 studies (ALL, n = 15; childhood leukemia, n = 14) reported in 32 articles. Most (>65%) included studies reported a positive association between infection variables and ALL or childhood leukemia. Among specific types of infection, we found that influenza during pregnancy was associated with higher risk of ALL (pooled OR, 3.64; 95% CI, 1.34-9.90) and childhood leukemia (pooled OR, 1.77; 95% CI, 1.01-3.11). Varicella (pooled OR, 10.19; 95% CI, 1.98-52.39) and rubella (pooled OR, 2.79; 95% CI, 1.16-6.71) infections were also associated with higher childhood leukemia risk. CONCLUSIONS: Our findings suggest that maternal infection during pregnancy may be associated with a higher risk of childhood leukemia.

Paediatric acute lymphoblastic leukaemia and caesarean section: A report from the United Kingdom Childhood Cancer Study (UKCCS).

BACKGROUND: Reports have suggested that children born by caesarean initiated before labour onset may be at increased risk of developing acute lymphoblastic leukaemia (ALL). However, with most data being derived from case-control study interviews, information on the underpinning reasons for caesarean section is sparse, and evidence is conflicting. OBJECTIVES: Use clinical records compiled at the time of delivery to investigate the association between childhood ALL and caesarean delivery; examining timing in relation to labour onset, and reasons for the procedure. METHODS: Data are from the UK Childhood Cancer Study, a population-based case-control study conducted in the 1990s, when caesarean section rates were relatively low, in England, Scotland, and Wales. Children with ALL were individually matched to two controls on sex, date of birth, and region of residence. Information on mode of delivery and complications was abstracted from obstetric records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models adjusted for matching variables and relevant covariates. RESULTS: Around 75% of the 1034 cases and 1914 controls were born through unassisted vaginal delivery. Caesarean delivery was as frequent in cases and controls (OR 1.07, 95% CI 0.84, 1.36). No association was observed between ALL and caesarean delivery either during or before labour, with adjusted ORs of 1.08 (95% CI 0.78, 1.48) and 1.09 (95% CI 0.78, 1.53), respectively. For B-cell ALL, the ORs were 1.14 (95% CI 0.81, 1.59) for caesarean during labour and 1.21 (95% CI 0.85, 1.72) for prelabour. The underpinning reasons for caesarean delivery differed between cases and controls; with preeclampsia, although very rare, being more common amongst cases born by caesarean (OR 8.91, 95% CI 1.48, 53.42). CONCLUSIONS: Our obstetric record-based study found no significant evidence that caesarean delivery increased the risk of childhood ALL, either overall or when carried out before labour.

Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.

Childhood cancer incidence and survival in Japan and England: A population-based study (1993-2010).

The present study aimed to compare cancer incidence and trends in survival for children diagnosed in Japan and England, using population-based cancer registry data. The analysis was based on 5192 children with cancer (age 0-14 years) from 6 prefectural cancer registries in Japan and 21 295 children diagnosed in England during 1993-2010. Differences in incidence rates between the 2 countries were measured with Poisson regression models. Overall survival was estimated using the Kaplan-Meier method. Incidence rates for Hodgkin lymphoma, renal tumors and Ewing sarcomas in England were more than twice as high as those in Japan. Incidence of germ cell tumors, hepatic tumors, neuroblastoma and acute myeloid leukemia (AML) was higher in Japan than in England. Incidence of all cancers combined decreased in Japan throughout the period 1993 to 2010, which was mainly explained by a decrease in registration of neuroblastoma in infants. For many cancers, 5-year survival improved in both countries. The improvement in survival in chronic myeloid leukemia (CML) was particularly dramatic in both countries. However, 5-year survival remained less than 80% in 2005-2008 in both countries for AML, brain tumors, soft tissue sarcomas, malignant bone tumors and neuroblastoma (age 1-14 years). There were significant differences in incidence of several cancers between countries, suggesting variation in genetic susceptibility and possibly environmental factors. The decrease in incidence for all cancers combined in Japan was related to the cessation of the national screening program for neuroblastoma. The large improvement in survival in CML coincided with the introduction of effective therapy (imatinib).

Adult leukemia survival trends in the United States by subtype: A population-based registry study of 370,994 patients diagnosed during 1995-2009.

BACKGROUND: The lifetime risk of developing leukemia in the United States is 1.5%. There are challenges in the estimation of population-based survival using registry data because treatments and prognosis vary greatly by subtype. The objective of the current study was to determine leukemia survival estimates in the United States from 1995 to 2009 according to subtype, sex, geographical area, and race. METHODS: Five-year net survival was estimated using data for 370,994 patients from 43 registries in 37 states and in 6 metropolitan areas, covering approximately 81% of the adult (15-99 years) US population. Leukemia was categorized according to principal subtype (chronic lymphocytic leukemia, acute myeloid leukemia, and acute lymphocytic leukemia), and subcategorized in accordance with the HAEMACARE protocol. We analyzed age-standardized 5-year net survival by calendar period (1995-1999, 2000-2004, and 2005-2009), leukemia subtype, sex, race, and US state. RESULTS: The age-standardized 5-year net survival estimates increased from 45.0% for patients diagnosed during 1995-1999 to 49.0% for those diagnosed during 2000-2004 and 52.0% for those diagnosed during 2005-2009. For patients diagnosed during 2005-2009, 5-year survival was 18.2% (95% confidence interval [95% CI], 17.8%-18.6%) for acute myeloid leukemia, 44.0% (95% CI, 43.2%-44.8%) for acute lymphocytic leukemia, and 77.3% (95% CI, 76.9%-77.7%) for chronic lymphocytic leukemia. For nearly all leukemia subtypes, survival declined in successive age groups above 45 to 54 years. Men were found to have slightly lower survival than women; however, this discrepancy was noted to have fallen in successive calendar periods. Net survival was substantially higher in white than black patients in all calendar periods. There were large differences in survival noted between states and metropolitan areas. CONCLUSIONS: Survival from leukemia in US adults improved during 1995-2009. Some geographical differences in survival may be related to access to care. We found disparities in survival by sex and between black and white patients.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: a pooled analysis from the childhood Leukemia International Consortium.

PURPOSE: The early onset of childhood acute lymphoblastic leukemia (ALL) suggests that critical exposures occurring during pregnancy may increase risk. We investigated the effects of maternal coffee and tea consumption during pregnancy on ALL risk by pooling data from eight case-control studies participating in the Childhood Leukemia International Consortium. METHOD: Data on maternal coffee intake were available for 2,552 cases and 4,876 controls, and data on tea intake were available for 2,982 cases and 5,367 controls. Coffee and tea intake was categorized into 0, > 0-1, > 1-2, and > 2 cups/day, and covariates were combined and harmonized. Data on genetic variants in NAT2, CYP1A1, and NQO1 were also available in a subset. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, and linear trends across categories were assessed. RESULTS: No association was seen with 'any' maternal coffee consumption during pregnancy, but there was evidence of a positive exposure-response; the pooled OR for > 2 cups/day versus none was 1.27 (95% CI 1.09-1.43), p trend = 0.005. No associations were observed with tea consumption. No interactions were seen between coffee or tea intake and age, maternal smoking or genotype, and there was little or no evidence that associations with coffee or tea differed among cases with and without chromosomal translocations. CONCLUSIONS: Despite some limitations, our findings suggest that high coffee intake during pregnancy may increase risk of childhood ALL. Thus, current advice to limit caffeine intake during pregnancy to reduce risk of preterm birth may have additional benefits.

Temporal trends in the proportion of "cure" in children, adolescents, and young adults diagnosed with chronic myeloid leukemia in England: A population-based study.

BACKGROUND: Survival probability in children, adolescents, and young adults with chronic myeloid leukemia (CML) has dramatically improved during recent years. Tyrosine kinase inhibitors (TKI), targeted drugs developed for patients with CML, were introduced in 2001 in England. We here quantify the trends in the "cure" proportion according to the year of diagnosis. METHODS: We included all children, adolescents, and young patients with CML (0 to 24 years) diagnosed in England during 1980 to 2005. We fitted mixture cure models to estimate the "cure" proportion and the median survival time among the "uncured" patients according to the year of diagnosis, adjusted for age at diagnosis. RESULTS: The "cure" proportion increased dramatically between 1980 and 2005, from under 10% to over 80%, while conversely, the median survival time of "uncured" patients decreased slightly between 1980 and 1999, with the trend from 2000 being uncertain. CONCLUSIONS: The striking improvement of the "cure" fraction in young patients with CML since the early 1980s is concomitant with improvement of treatment, especially the allogeneic hematopoietic stem-cell transplant and, later, the introduction of TKI. The trends over the last years (2000-2005) remain, however, uncertain and would benefit from further studies with more recent data and updated follow-up.

Survival among children diagnosed with acute lymphoblastic leukemia in the United States, by race and age, 2001 to 2009: Findings from the CONCORD-2 study.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. This report describes the survival of children with ALL in the United States using the most comprehensive and up-to-date cancer registry data. METHODS: Data from 37 state cancer registries that cover approximately 80% of the US population were used. Age-standardized survival up to 5 years was estimated for children aged 0-14 years who were diagnosed with ALL during 2 periods (2001-2003 and 2004-2009). RESULTS: In total, 17,500 children with ALL were included. The pooled age-standardized net survival estimates for all US registries combined were 95% at 1 year, 90% at 3 years, and 86% at 5 years for children diagnosed during 2001-2003, and 96%, 91%, and 88%, respectively, for those diagnosed during 2004-2009. Black children who were diagnosed during 2001-2003 had lower 5-year survival (84%) than white children (87%) and had less improvement in survival by 2004-2009. For those diagnosed during 2004-2009, the 1-year and 5-year survival estimates were 96% and 89%, respectively, for white children and 96% and 84%, respectively, for black children. During 2004-2009, survival was highest among children aged 1 to 4 years (95%) and lowest among children aged <1 year (60%). CONCLUSIONS: The current results indicate that overall net survival from childhood ALL in the United States is high, but disparities by race still exist, especially beyond the first year after diagnosis. Clinical and public health strategies are needed to improve health care access, clinical trial enrollment, treatment, and survivorship care for children with ALL. Cancer 2017;123:5178-89. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Population-based cancer survival in the United States: Data, quality control, and statistical methods.

BACKGROUND: Robust comparisons of population-based cancer survival estimates require tight adherence to the study protocol, standardized quality control, appropriate life tables of background mortality, and centralized analysis. The CONCORD program established worldwide surveillance of population-based cancer survival in 2015, analyzing individual data on 26 million patients (including 10 million US patients) diagnosed between 1995 and 2009 with 1 of 10 common malignancies. METHODS: In this Cancer supplement, we analyzed data from 37 state cancer registries that participated in the second cycle of the CONCORD program (CONCORD-2), covering approximately 80% of the US population. Data quality checks were performed in 3 consecutive phases: protocol adherence, exclusions, and editorial checks. One-, 3-, and 5-year age-standardized net survival was estimated using the Pohar Perme estimator and state- and race-specific life tables of all-cause mortality for each year. The cohort approach was adopted for patients diagnosed between 2001 and 2003, and the complete approach for patients diagnosed between 2004 and 2009. RESULTS: Articles in this supplement report population coverage, data quality indicators, and age-standardized 5-year net survival by state, race, and stage at diagnosis. Examples of tables, bar charts, and funnel plots are provided in this article. CONCLUSIONS: Population-based cancer survival is a key measure of the overall effectiveness of services in providing equitable health care. The high quality of US cancer registry data, 80% population coverage, and use of an unbiased net survival estimator ensure that the survival trends reported in this supplement are robustly comparable by race and state. The results can be used by policymakers to identify and address inequities in cancer survival in each state and for the United States nationally. Cancer 2017;123:4982-93. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Life tables for global surveillance of cancer survival (the CONCORD programme): data sources and methods.

BACKGROUND: We set out to estimate net survival trends for 10 common cancers in 279 cancer registry populations in 67 countries around the world, as part of the CONCORD-2 study. Net survival can be interpreted as the proportion of cancer patients who survive up to a given time, after eliminating the impact of mortality from other causes (background mortality). Background mortality varies widely between populations and over time. It was therefore necessary to construct robust life tables that accurately reflected the background mortality in each of the registry populations. METHODS: Life tables of all-cause mortality rates by single year of age and sex were constructed by calendar year for each population and, when possible, by racial or ethnic sub-groups. We used three different approaches, based on the type of mortality data available from each registry. With death and population counts, we adopted a flexible multivariable modelling approach. With unsmoothed mortality rates, we used the Ewbank relational method. Where no data were available from the registry or a national statistical office, we used the abridged UN Population Division life tables and interpolated these using the Elandt-Johnson method. We also investigated the impact of using state- and race-specific life tables versus national race-specific life tables on estimates of net survival from four adult cancers in the United States (US). RESULTS: We constructed 6,514 life tables covering 327 populations. Wide variations in life expectancy at birth and mortality by age were observed, even within countries. During 1995-99, life expectancy was lowest in Nigeria and highest in Japan, ranging from 47 to 84 years among females and 46 to 78 years among males. During 2005-09, life expectancy was lowest in Lesotho and again highest in Japan, ranging from 45 to 86 years among females and 45 to 80 years among males. For the US, estimates of net survival differed by up to 4% if background mortality was fully controlled with state- and race-specific life tables, rather than with national race-specific life tables. CONCLUSIONS: Background mortality varies worldwide. This emphasises the importance of using population-specific life tables for geographic and international comparisons of net survival.

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. FUNDING: Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

Risk factors for childhood brain tumours: A systematic review and meta-analysis of observational studies from 1976 to 2022.

BACKGROUND: Childhood brain tumours (CBTs) are the leading cause of cancer death in children under the age of 20 years globally. Though the aetiology of CBT remains poorly understood, it is thought to be multifactorial. We aimed to synthesize potential risk factors for CBT to inform primary prevention. METHODS: We conducted a systematic review and meta-analysis of epidemiological studies indexed in the PubMed, Web of Science, and Embase databases from the start of those resources through 27 July 2023. We included data from case-control or cohort studies that reported effect estimates for each risk factor around the time of conception, during pregnancy and/or during post-natal period. Random effects meta-analysis was used to estimate summary effect sizes (ES) and 95% confidence intervals (CIs). We also quantified heterogeneity (I2) across studies. FINDINGS: A total of 4040 studies were identified, of which 181 studies (85 case-control and 96 cohort studies) met our criteria for inclusion. Of all eligible studies, 50% (n = 91) were conducted in Europe, 32% (n = 57) in North America, 9% (n = 16) in Australia, 8% (n = 15) in Asia, 1% (n = 2) in South America, and none in Africa. We found associations for some modifiable risk factors including childhood domestic exposures to insecticides (ES 1.44, 95% CI 1.20-1.73) and herbicides (ES 2.38, 95% CI 1.31-4.33). Maternal domestic exposure to insecticides (ES 1.45, 95% CI 1.09-1.94), maternal consumption of cured meat (ES 1.51, 95% CI 1.05-2.17) and coffee ≥ 2 cups/day (ES 1.45, 95% 95% CI 1.07-1.95) during pregnancy, and maternal exposure to benzene (ES 2.22; 95% CI 1.01-4.88) before conception were associated with CBTs in case-control studies. Also, paternal occupational exposure to pesticides (ES 1.48, 95% CI 1.23-1.77) and benzene (ES 1.74, 95% CI 1.10-2.76) before conception and during pregnancy were associated in case-control studies and in combined analysis. On the other hand, assisted reproductive technology (ART) (ES 1.32, 95% CI 1.05-1.67), caesarean section (CS) (ES 1.12, 95% CI 1.01-1.25), paternal occupational exposure to paint before conception (ES 1.56, 95% CI 1.02-2.40) and maternal smoking > 10 cigarettes per day during pregnancy (ES 1.18, 95% CI 1.00-1.40) were associated with CBT in cohort studies. Maternal intake of vitamins and folic acid during pregnancy was inversely associated in cohort studies. Hormonal/infertility treatment, breastfeeding, child day-care attendance, maternal exposure to electric heated waterbed, tea and alcohol consumption during pregnancy were among those not associated with CBT in both case-control and cohort studies. CONCLUSION: Our results should be interpreted with caution, especially as most associations between risk factors and CBT were discordant between cohort and case-control studies. At present, it is premature for any CBT to define specific primary prevention guidelines.

Folate metabolism and risk of childhood acute lymphoblastic leukemia: a genetic pathway analysis from the Childhood Cancer and Leukemia International Consortium.

BACKGROUND: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity, and led to inconclusive results. METHODS: We evaluated whether ~2,900 single nucleotide polymorphisms (SNPs) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control-studies in the Childhood Cancer and Leukemia International Consortium (n=9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data, and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni p-value of 5x10-6 and less stringent p-value of 3.5x10-5 accounting for the number of "independent" SNPs). None of the 10 top (non-significant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSION: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT: Genetic variants in the folate pathway alone do not appear to substantially influence childhood ALL risk. Other mechanisms such as gene-folate interaction, DNA methylation or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). METHODS: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. FINDINGS: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. INTERPRETATION: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. FUNDING: Bill & Melinda Gates Foundation.

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. METHODS: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. FINDINGS: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. INTERPRETATION: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. FUNDING: Bill & Melinda Gates Foundation.